EP2286847A1 - Formulations of hyaluronic acid for delivery of osteogenic proteins - Google Patents

Formulations of hyaluronic acid for delivery of osteogenic proteins Download PDF

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Publication number
EP2286847A1
EP2286847A1 EP10182996A EP10182996A EP2286847A1 EP 2286847 A1 EP2286847 A1 EP 2286847A1 EP 10182996 A EP10182996 A EP 10182996A EP 10182996 A EP10182996 A EP 10182996A EP 2286847 A1 EP2286847 A1 EP 2286847A1
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EP
European Patent Office
Prior art keywords
composition
hyaff
bmp
hyaluronic acid
bone
Prior art date
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Withdrawn
Application number
EP10182996A
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German (de)
English (en)
French (fr)
Inventor
Hyun Kim
Rebecca Li
Lanfranco Callegaro
Allesandra Pavesio
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Anika Therapeutics SRL
Genetics Institute LLC
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Fidia Advanced Biopolymers SRL
Genetics Institute LLC
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Application filed by Fidia Advanced Biopolymers SRL, Genetics Institute LLC filed Critical Fidia Advanced Biopolymers SRL
Priority claimed from EP04017645A external-priority patent/EP1481695A1/en
Publication of EP2286847A1 publication Critical patent/EP2286847A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions

Definitions

  • the subject invention relates to the field of osteogenic proteins and pharmaceutical formulations thereof. More particularly, the subject invention involves injectable pharmaceutical formulations comprising hyaluronic acid derivitives and osteogenic proteins. The invention further provides methods for formulating porous injectable gels and pastes from hyaluronic acid.
  • Osteogenic proteins are those proteins capable of inducing, or assisting in the induction of, cartilage and/or bone formation. Many such osteogenic proteins have in recent years been isolated and characterized, and some have been produced by recombinant methods. For example, so-called bone morphogenic proteins (BMP) have been isolated from demineralized bone tissue (see e.g. Urist US 4,455,256 ); a number of such BMP proteins have been produced by recombinant techniques (see e.g. Wang et al. US 4,877,864 and Wang et al. US 5,013,549 ); a family of transforming growth factors (TGF- ⁇ and TGF- ⁇ ) has been identified as potentially useful in the treatment of bone disease (see e.g.
  • a biodegradable matrix of porous particles for delivery of an osteogenic protein designated as OP is disclosed in Kuber A. Sampath, U.S. 5,108,753 .
  • United States Patent 4,645,503 discloses composites of hydroxyapatite and Plaster of Paris as bone implant materials.
  • Collagen matrices have also been used as delivery vehicles for osteogenic proteins (see e.g. Jeffries, U.S. 4,394,370 ).
  • the present invention provides injectable formulations for delivery of osteogenic proteins.
  • the composition comprises the osteogenic protein and hyaluronic acid esters.
  • the composition may further include tricalcium phosphate.
  • the injectable formulations of the invention allows for closed fracture repair and other skeletal tissue without an open reduction procedure as is necessary with implantable devices.
  • the present invention further provides methods for preparing injectable gels or pastes useful as a carrier for osteogenic proteins by transforming various non-woven pads and sponges of hyaluronic acid benzyl ester into injectable gel or paste formulations by hydration or solvent addition.
  • the invention comprises compositions comprising the transformed injectable gel or paste formulations.
  • the methods and compositions of the present invention are useful for the preparation of formulations of osteoinductive proteins which can be used, among other uses, to promote the formation of cartilage and/or bone, for repair of tissue damage and fractures.
  • the invention further provides methods for treating patients in need of cartilage and/or bone repair and/or growth.
  • the invention provides injectable formulations for delivery of osteogenic proteins.
  • compositions comprise an injectable formulation of hyaluronic acid esters and osteogenic protein.
  • the present invention further provides processes for preparing injectable gel or paste formulations by transforming various non-woven pads and sponges of hyaluronic acid benzyl ester by hydration or solvent addition yielding gels with in vivo residence times from days to up to several months.
  • Total or partial esters of hyaluronic acid are described in US 5,336,767 .
  • Partial esters of Hyaff solids are transformed into gels using aqueous buffer or organic solvents (such as N-methyl pyrrolidinone, dimethyl sulfoxide, etc), while complete esters of Hyaff solids are transformed into gels using organic solvents.
  • pore formers may be introduced to the solublized carriers to increase porosity.
  • the addition of pore formers would allow in situ pore formation after injection in vivo by solubilization of pore former and precipitation/phase inversion of carrier.
  • Suitable liquid pore formers include polyethylene glycol or PEG at 10 - 90 % volume per volume ratios) and solid pore formers (such as sodium bicarbonate, sodium chloride, citric acid, sucrose, etc., at 1:1 - 21:1 pore former:Hyaff weight per weight ratios) to increase porosity.
  • the gel/paste can also contain TCP (tri-calcium phosphate) particles as a mineral component for example, at 0.1 - 100 % weight per volume range.
  • the amount, type and size of the pore forming agent is optimized to leave voids sufficient for cell ingrowth into injectable gel when pore forming agent and solvent are extracted from the carrier in vivo by solubilization of pore forming agent and precipitation/phase inversion of carrier in situ.
  • the osteogenic proteins useful with the injectable carriers made in accordance with the subject invention are well known to those skilled in the art and include those discussed above.
  • the preferred osteogenic proteins for use herein are those of the BMP class identified as BMP-1 through BMP-12 in US 4,877,864 ; US 5,013,649 ; WO 90/11366 published October 4, 1990 ; WO 91/18098 published November 28, 1991 ; WO 93/00432, published January 7, 1993 ; United States Serial Numbers 08/247,908 and 08/247,904, both filed May 20, 1994 ; and United States Serial Number 08/217,780, filed on March 25, 1994 .
  • the disclosure of the above publications are hereby incorporated by reference.
  • BMP-2 the full length cDNA sequence of which is described in detail in the '649 patent.
  • combinations of two or more of such osteogenic proteins may be used, as may fragments of such proteins that also exhibit osteogenic activity.
  • Such osteogenic proteins are known to be homodimeric species, but also exhibit activity as mixed heterodimers. Heterodimeric forms of osteogenic proteins may also be used in the practice of the subject invention.
  • BMP heterodimers are described in WO93/09229 , the disclosure of which is hereby incorporated by reference. Recombinant proteins are preferred over naturally occurring isolated proteins.
  • the amount of osteogenic protein useful herein is that amount effective to stimulate increased osteogenic activity of infiltrating progenitor cells, and will depend upon the size and nature of defect being treated as well as the carrier being employed.
  • the formulations may be injected for example into tendons, damaged cartilage tissue, ligaments, and/or their attachment sites to bones. Injectable formulations may also find application to other bone sites such as bone cysts, bone defects, intraosseous sites and closed fractures.
  • the dosage regimen will be determined by the clinical indication being addressed, as well as by various patient variables (e.g. weight, age, sex) and clinical presentation (e.g. extent of injury, site of injury, etc.).
  • the dosage of osteogenic protein will be in the range of from about 0.1 to 4 mg/ml.
  • the injectable osteogenic protein formulations may be provided to the clinic as a single formulation, or the formulation may be provided as a multicomponent kit wherein, e.g. the osteogenic protein is provided in one vial and the injectable hyaluronic paste is provided separately.
  • compositions of the subject invention allow therapeutically effective amounts of osteoinductive protein to be delivered to an injury site where cartilage and/or bone formation is desired.
  • the formulations may be used as a substitute for autologous bone graft in fresh and non-union fractures, spinal fusions, and bone defect repair in the orthopaedic field; in cranio/maxillofacial reconstructions; for prosthesis integration, especially as a surface coating to improve fixation of prosthetic implants such as hydroxyapatite coated prostheses; in osteomyelitis for bone regeneration; and in the dental field for augmentation of the alveolar ridge and periodontal defects and tooth extraction sockets.
  • the methods and formulations of the present invention may be useful in the treatment and/or prevention of osteoporosis, or the treatment of osteoporotic or osteopenic bone.
  • formulations of the present invention may be used in the process known as distraction osteogenesis.
  • the osteogenic protein When used to treat osteomyelitis or for bone repair with minimal infection, the osteogenic protein may be used in combination with porous microparticles and antibiotics, with the addition of protein sequestering agents such as alginate, cellulosics, especially carboxymethylcellulose, diluted using aqueous glycerol.
  • the antibiotic is selected for its ability to decrease infection while having minimal adverse effects on bone formation.
  • Preferred antibiotics for use in the devices of the present invention include vancomycin and gentamycin.
  • the antibiotic may be in any pharmaceutically acceptable form, such as vancomycin HCl or gentamycin sulfate.
  • the antibiotic is preferably present in a concentration of from about 0.1 mg/mL to about 10.0 mg/mL.
  • the traditional preparation of formulations in pharmaceutically acceptable form i.e. pyrogen free, appropriate pH and isotonicity, sterility, etc. is well within the skill in the art and is applicable to the formulations of the invention.
  • Hyaluronic derivitive compositions of the invention prepared by hydration or solvent addition of insoluble or partially soluble non- woven pads or sponges may also be ultilized in combination with other drugs, growth factors, peptides, proteins, cytokines, oligonucleeotides antisense oligonucleotides, DNA and polymers. These compounds may be added by mixing them with the carriers. Or by covalent attachment to the polymer carriers.
  • the hyaluronic derivitive compositions may also be used with DNA encoding for BMPs and cells transduced or transfected with genes encoding BMP proteins.
  • the starting Hyaff hyaluronic acid (Fidia Advanced Biopolymers, Abano Terme, Italy) materials are solids such as non-woven pads, felts, sheets, powders, sponges, and microspheres.
  • the Hyaff materials are esters of hyaluronic acid exhibiting various ester moities (e.g., benzyl, ethyl,propyl pentyl or larger molecules such as hydrocortisone or methyl prednislone, etc.) as well as various degrees of esterification (i.e., partial esters or complete esters).
  • Hyaff gel classification used in supporting data is as follows and is followed by examples of select formulations:
  • Hyaff-11p65 non-woven pads were hydrated with glutamic acid buffer (pH 4.5) containing rhBMP-2 (0.1mg/mL final conc.) to yield either 6 % - 15 % solids (w/v) and mixed thoroughly to form a paste.
  • Hyaff-11p80 and Hyaff-11 non-woven pads were solubilized in N-methyl-pyrrolidinone (NMP) or dimethyl sulfoxide(DMSO)to yield a 1 - 30 % w/v solution.
  • NMP N-methyl-pyrrolidinone
  • DMSO dimethyl sulfoxide
  • rhBMP-2-containing buffer 10 % v/v, 0.1 mg/mL rhBMP-2
  • lyophilized rhBMP-2 0.1 mg/mL
  • various pore formers polyethylene glycol, sodium bicarbonate, sucrose, NaCl, citric acid
  • TCP tricalcium phosphate
  • Particle size of solid pore formers and TCP used was ⁇ 600um, preferably ⁇ 200umLiquid pore formers such as PEG(200mw) were mixed at 10-90% v/v ratios, and solid pore formers were mixed at 9:1 - 21:1 (w/w) pore former to carrier ratios.
  • TCP was mixed at 0.1-30% (w/v).
  • TCP 45-125 micron particle size
  • rhBMP-2 was adsorbed onto TCP first, followed by mixing with Hyaff-11 or Hyaff-11p65 gel.Formulations were chosen based on injectability through an 18 g needle.
  • Microstructure was characterized by scanning electron microscopy (SEM).
  • Hyaff-11p65 6% gel exhibited longer fibers than the 15% formulation; with both displaying a high level of porosity.
  • Both Hyaff-11 and Hyaff-11p80 gels showed minimal pore structure and porosity, whereas those carriers with pore formers displayed a high level of porosity.
  • Pore formers and/ or additives that yielded injectable mixtures were PEG, sodium bicarbonate and TCP.
  • 125 I-rhBMP-2 loaded samples (50,000 cpm/sample) were incubated in 1 ml fetal calf serum (Hyclone) at 37°C on a shaker, and radioactivity of the carrier measured up to 14 days using a gamma counter. Fresh serum was replaced after each time point.
  • 125 I-rhBMP-2 release from injectable formulations were compared to those of implantable sponges and pads of Hya-11 and Hyaff-11 p80.
  • ACP gel Auto cross-linked polysaccharide form of derivitized hyaluronic acid, ACP gel, is used for the in vitro release study and the rat ectopic assay.
  • ACP gel 2 ml ACP gel is mixed with 1.53 mg rhBMP-2 cake (which corresponds to 0.2 mg actual rhBMP-2 at 8 mg rhBMP-2 per 61 mg cake weight) and 125 I-rhBMP-2 (100 ml total, 20 mCi/200 ml gel) and drawn up into 1 ml syringes resulting in approximately 10 % gel dilution.
  • ACP gel for the rat ectopic study does not contain the tracer but is diluted with MRF-00906 buffer. 200 ml injections are performed using a 22 gauge needle. The final concentration of rhBMP-2 will be 0.1 mg/ml, or 20 mg per 200 ml injection. The final concentration of 125 I-rhBMP-2 will be approximately 20 mCi per 200 ml injection. The ACP gel will be injected at room temperature.
  • Hyaff-11p65 gel released rhBMP-2 the fastest. Sponges and pads of Hyaff-11 and Hyaff-11p80 retained less rhBMP-2 than Hyaff-11/PEG or Hyaff-11p80 gel, but more than Hyaff-11p65. Addition of TCP to Hyaff-11 gel increased rhBMP-2 retention. The release profile in all carriers exhibited moderate to rapid burst release followed by a slow, sustained release of rhBMP-2. All Hyaff-11 and Hyaff-11p80 gel formulations retained rhBMP-2 well (> 50 % remaining after 14 days) except Hyaff-11p65.
  • Hyaff-11 based gels formed significant ectopic bone in the rat model (Table 1) in the presence of rhBMP-2, although differences in bone formation existed between carrier types as confirmed by radiographs and histology.
  • Hyaff-11p65 at varying doses (0.1-1.5 mg/mL) of rhBMP-2 exhibited a dose dependent increase in bone formation (and bone score) but was inconsistent in explant size which yielded less total bone (0.1 mg/mL rhBMP-2 data shown).
  • Hyaff-11p80 explants were large but had a lower bone score, while Hyaff-11 showed good bone score and total bone.
  • Hyaff-11/PEG and Hyaff-11/sodium bicarbonate radiographically showed equivalent radioopacity as those of Hyaff-11 and Hyaff-11p80.
  • both Hyaff-11 and Hyaff-11p80 carriers showed residual remaining matrix due to their slow degradation rates, although Hyaff-11p65 completely degraded by 2 weeks. Bone formed within pores, shown by mineralizing osteoblasts as well as through a cartilage intermediate. Addition of TCP to Hyaff-11 gel with or without pore formers also showed comparableradiographic evidence of bone formation as those of other Hyaff based gels.
  • Table 1 Histomorphometry results of rat ectopic bone formation assay.
  • 125 I-rhBMP-2 loaded samples (50,000 cpm/sample) were incubated in 1 mL fetal calf serum (Hyclone) at 37°C on a shaker, and radioactivity of the carrier measured up to 14 days using a gamma counter.. Fresh serum was replaced after 1, 3, 7, and 14 days.
  • Hyaff-11/TCP retained the most rhBMP-2, followed by Hyaff- 11, Hyaff-11p65/TCP, and Hyaff-11p65.
  • Hyaff-11 retained more rhBMP-2 than Hyaff-11p65 due to its hydrophobicity and insolubility.
  • Preadsorbing rhBMP-2 on TCP increased rhBMT-2 retention in Hyaff-11 gel, as opposed to mixing rhBMP-2 into the Hyaff-11 phase.
  • Preadsorbing or mixing rhBMP-2 into either TCP or Hyaff-11p65 phase resulted in similar rhBMP-2 retention, both of which were greater than Hyaff-11p65 without TCP.
  • Retention of rhBNIP-2 within Hyaff-11/TCP and Hyaff-11p65/TCP was analyzed in vivo using a rabbit ulna fracture model.
  • Amount of radioactivity left within each carrier at the fracture site was measured by gamma scintigraphy over the course of several weeks and in vivo rhBMP-2 retention calculated over time.

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EP10182996A 1999-10-15 2000-10-13 Formulations of hyaluronic acid for delivery of osteogenic proteins Withdrawn EP2286847A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US15967499P 1999-10-15 1999-10-15
US18558700P 2000-02-28 2000-02-28
EP04017645A EP1481695A1 (en) 1999-10-15 2000-10-13 Formulations of hyaluronic acid for delivery of osteogenic proteins
EP00970914A EP1223990B1 (en) 1999-10-15 2000-10-13 Formulations of hyaluronic acid for delivery of osteogenic proteins

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EP00970914.8 Division 2000-10-13
EP04017645.5 Division 2004-07-26

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EP00970914A Revoked EP1223990B1 (en) 1999-10-15 2000-10-13 Formulations of hyaluronic acid for delivery of osteogenic proteins

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EP (2) EP2286847A1 (https=)
JP (1) JP4703926B2 (https=)
AT (1) ATE271886T1 (https=)
AU (2) AU774427B2 (https=)
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DE (1) DE60012557T2 (https=)
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ES (1) ES2225241T3 (https=)
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
RU2533017C1 (ru) * 2013-06-25 2014-11-20 Федеральное государственное бюджетное учреждение "Саратовский научно-исследовательский институт травматологии и ортопедии" Министерства здравоохранения Российской Федерации (ФГБУ "СарНИИТО" Минздрава России) Способ лечения кистозных образований длинных трубчатых костей

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Publication number Priority date Publication date Assignee Title
US20070026437A1 (en) * 1988-04-08 2007-02-01 Genetics Institute, L.L.C. Novel BMP products
US7582311B1 (en) * 1999-10-15 2009-09-01 Genentech, Inc. Injection vehicle for polymer-based formulations
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